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Generation of extracellular morphogen gradients: the case for diffusion

Abstract

Cells within developing tissues rely on morphogens to assess positional information. Passive diffusion is the most parsimonious transport model for long-range morphogen gradient formation but does not, on its own, readily explain scaling, robustness and planar transport. Here, we argue that diffusion is sufficient to ensure robust morphogen gradient formation in a variety of tissues if the interactions between morphogens and their extracellular binders are considered. A current challenge is to assess how the affinity for extracellular binders, as well as other biophysical and cell biological parameters, determines gradient dynamics and shape in a diffusion-based transport system. Technological advances in genome editing, tissue engineering, live imaging and in vivo biophysics are now facilitating measurement of these parameters, paving the way for mathematical modelling and a quantitative understanding of morphogen gradient formation and modulation.

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Fig. 1: Tissue architecture and boundary conditions.
Fig. 2: Morphogen transport models.
Fig. 3: Lipid-shielding mechanisms.
Fig. 4: Morphogen gradient regulation by extracellular interactors.
Fig. 5: Engineering diffusion-based GFP gradients in vitro and in vivo.

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Acknowledgements

The authors are particularly indebted to the reviewers, who provided exceptionally insightful feedback. Work in the laboratory of J.-P.V. is supported by a Wellcome Trust Investigator Award (206341/Z/17/Z), as well as the Francis Crick Institute, which receives its core funding from Cancer Research UK (no. FC001204), the UK Medical Research Council (no. FC001204) and the Wellcome Trust (no. FC001204). K.S.S. was a recipient of a PhD. studentship from the Wellcome Trust (109054/ Z/15/Z). The authors acknowledge the significant insight they gained from discussions with L. Cocconi, M. DeGennes and G. Salbreux.

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K.S.S. researched data for the article. K.S.S. and J.-P.V. made substantial contributions to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Jean-Paul Vincent.

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Glossary

French flag model

A model in which different concentration thresholds of a single signalling molecule can instruct distinct cell fates and therefore enable a concentration gradient of such a signalling molecule to pattern an underlying tissue.

Syncytial

Refers to a multinucleated cell.

Pleiotropic

Refers to genes or proteins that can cause multiple phenotypes.

Optogenetic

Refers to experimental methods involving the use of light-sensitive proteins to control cellular processes by light.

Exosomes

Extracellular membranous vesicles that originate from inward budding events of the endosomal membrane.

Micelles

Spherical aggregates of amphiphilic molecules that have a hydrophobic core and a hydrophilic shell.

Glypicans

Heparan sulfate proteoglycans that are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI).

Stokes radius

The radius of a hypothetical hard sphere with the same diffusion properties as the solute.

Tortuosity

The increased path length that molecules have to cover when diffusing from one point to another through the convoluted geometry of the extracellular matrix.

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Stapornwongkul, K.S., Vincent, JP. Generation of extracellular morphogen gradients: the case for diffusion. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00342-y

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